II SESSIONE: “GENITO-URINARIO”
Opzioni terapeutiche nel carcinoma prostatico metastatico sensibile alla castrazione (mHSPC)
Dott. Davide Bimbatti UOC Oncologia Medica
AOUI Verona
Agenda
1. Standard initial treatment options 2. Chemotherapy: Docetaxel
3. Hormone therapy: Abiraterone
4. Next generation androgen receptor agonists 5. Patient choice
6. Future challenges
Standard initial treatment options - ADT
James ND et al. Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). Eur Urol 2015;67:1028-1038 Tangen CM et al. Improved Overall Survival Trends of Men
with Newly Diagnosed M1 Prostate Cancer: A SWOG Phase III Trial Experience (S8494, S8894 & S9346). The Journal of urology. 2012;188(4):1164-1169.
The Prostate Cancer Trialists’ Collaborative Group (PCTCG). Lancet 2000; 355: 1491–98
27 randomised trials involved 8275 men with metastatic (88%) or locally advanced (12%) prostate cancer.
Half were over 70 years of age, and follow-up was typically for about 5 years.
Addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%
Standard initial treatment options - ADT vs BAT
The Prostate Cancer Trialists’ Collaborative Group (PCTCG). Lancet 2000; 355: 1491–98
27 randomised trials involved 8275 men with metastatic (88%) or locally advanced (12%) prostate cancer.
Half were over 70 years of age, and follow-up was typically for about 5 years.
Addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%
Standard initial treatment options - ADT vs BAT
Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.
Standard initial treatment options - Intermittent
Standard initial treatment options - Intermittent
Hussain M et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. NEJM 2013;368(14):1314-1325.
Standard initial treatment options - ADT vs Bicalutamide
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
Chemotherapy - Docetaxel - CHAARTED
Inclusion Criteria:
• Pathological diagnosis of prostate cancer with elevated PSA
• Radiologic evidence of metastatic disease;
• ECOG 0, 1 or 2
• Prior adjuvant ADT was allowed if the duration of
therapy was 24 months or less and progression had occurred more than 12 months after completion of therapy.
• Patients who were receiving ADT for metastatic disease were eligible if there was no evidence of progression and treatment had commenced within 120 days before randomization.
R A N D O M I S E D 1:1
ADT+Docetaxel
ADT
Primary Outcome
• Overall Survival
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
Chemotherapy - Docetaxel - CHAARTED
High volume:
• presence of visceral metastases or
• ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis
Chemotherapy - Docetaxel - CHAARTED
Sweeney CJ et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. NEJM 2015 Aug 20;373(8):737-46.
James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016 Mar 19;387(10024):1163-77.
Chemotherapy - Docetaxel - STAMPEDE
Primary Outcome
• Overall Survival
James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016
Chemotherapy - Docetaxel - STAMPEDE
ADT+Docetaxel: mOS 81 months Hazard ratio for death with ADT+Docetaxel:
0.78 (95% CI, 0.66-0.93) P=0.006
ADT alone: mOS 71 months
Chemotherapy - Docetaxel - GETUG-15
Inclusion Criteria:
• Histologically confirmed adenocarcinoma
• Radiologically proven metastatic disease
• Karnofsky score ≥70%
• No previous chemotherapy for metastatic disease
• ADT for patients with metastatic disease could have been initiated no more than 2 months
• In the neo adjuvant and adjuvant settings or in the context of isolated PSA increase, previous
chemotherapy or ADT, or both, were allowed, with the condition that the treatment had been discontinued at least 12 months before inclusion
R A N D O M I S E D 1:1
ADT+Docetaxel
ADT
Gravis G et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–58
Primary Outcome
• Overall Survival
Chemotherapy - Docetaxel - GETUG-15
ADT+Docetaxel: mOS 58,9 months
Hazard ratio for death with ADT+Docetaxel:
1.01, (95% CI, 0.75-1.36) P=0.955
ADT alone: mOS 54,2 months
Gravis G et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate
Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. NEJM 2017 Jun 4
Hormone therapy - Abiraterone - LATITUDE
Inclusion Criteria:
• ECOG 0 to 2
• Newly diagnosed pathologically confirmed prostate cancer
• High-risk, metastatic, castration- sensitive prostate cancer.
• At least two of the three following high-risk factors: a Gleason score of 8 or more, at least 3 bone lesions, and the presence of measurable visceral metastasis.
• Allowed 3 months or less of androgen-deprivation or one course of palliative radiation or surgical therapy to treat
symptoms associated with metastatic disease.
R A N D O M I S E D 1:1
ADT+Abiraterone +prednisone
ADT+placebos
Primary Outcomes
• Overall Survival
• Radiographic Progression free survival
Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. NEJM 2017 Jun 4
Hormone therapy - Abiraterone - LATITUDE
ADT+Abiraterone:
3y OS 66%
ADT+placebos: 3y OS 49%
ADT+Abiraterone mrPFS: 33 m
ADT+placebos:
mrPFS 18,4 m
James ND et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. NEJM 2017 Jun 3
Hormone therapy - Abiraterone - STAMPEDE
Relapsing after previous RP or RT with ≥1 of:
• PSA ≥4ng/ml and rising with doubling time <6m
• PSA ≥20ng/ml
• Node-positive
• Metastatic Newly-diagnosed
Any of:
• Metastatic
• Node-Positive
• ≥2 of: Stage T3/4 PSA≥40ng/ml Gleason 8-10
Primary Outcome
• Overall Survival
Hormone therapy - Abiraterone - STAMPEDE
Events
262 Control | 184 abiraterone plus prednisone
HR 0.63
95% CI 0.52 to 0.76 P-value 0.00000115
SOC: 3y OS 76%
SOC+AAP: 3y OS 83%
Summary - Results
CHAARTED STAMPEDE
DOC GETUG 15 LATITUDE STAMPEDE ABI
mFU (months) 28,9 43 50 30,4 40
mOS (months) (HR)
57,6 vs 44 (0,61)
81 vs 71 (0,78)
58,9 vs 54,2
(1,01) NR vs 34,7 ND
3y OS (%) ̴70 vs 55 ̴77 vs 73 64,2 vs 62,9 66 vs 49 (0,62)
83 vs 76 (0,63) mFFS or mrPFS
(months) ND 37 vs 20 ND 33 vs 14,8 43,9 vs 30
3y FFS (%) ND ̴52 vs 39 ND ND 75 vs 45
Summary - Patients characteristics
CHAARTED STAMPEDE
DOC GETUG 15 LATITUDE STAMPEDE ABI
N+ o M+ (%) 100 75 100 100 70
M1 at
diagnosis (%) 100 58 70 100 50
High volume bone mets
*(%)
66 NA NA 98 NA
Visceral
disease (%) 15 ̴7 14 ̴14 <12
Gleason score
8-10 (%) 60 70 57 98 75
*CHAARTED: ≥4 with ≥1 beyond vertebral bodies and pelvis; LATITUDE: ≥3 lesions.
Next-generation androgen receptor (AR) antagonist - APALUTAMIDE
TITAN: STUDY DESIGN
Study population:
(estimated 1000 pts)
• Diagnosis of prostate adenocarcinoma.
• Metastatic disease documented by >= 1 bone lesions.
• ECOG PS grade of 0 or 1
• Permitted previous docetaxel treatment:
maximum of 6 cycles, last dose <=2 months, stable disease or better
• Other allowed prior treatment for mHSPC: a) Maximum of 1 course of radiation or surgical intervention;
radiation therapy for metastatic lesions must be completed prior to
randomization; b) Less than or equal to (<=) 6 months of ADT
• Allowed prior treatments for localized prostate
Primary Outcome
• Radiographic Progression-Free Survival
• Overall Survival
R A N D O M
I S E D 1:1
Apalutamide plus ADT
Placebo plus ADT
A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Subjects With Metastatic Hormone-sensitive Prostate Cancer (mHSPC).
ClinicalTrials.gov. NCT02489318
Next-generation androgen receptor (AR) antagonist - DAROLUTAMIDE
ARASENS: STUDY DESIGN
Study population:
(estimated 1300 pts)
• Histologically or cytologically confirmed adenocarcinoma of prostate.
• Metastatic disease
• Candidates for ADT and docetaxel.
Started ADT with or without first
generation anti androgen, but no longer than 12 weeks before randomization
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate bone marrow, liver and renal function
Primary Outcome
• Overall Survival
R A N D O M
I S E D 1:1
BAY1841788 /darolutamide
(ODM- 201)+standard ADT+Docetaxel
Placebo + standard ADT +
Docetaxel
A Randomized, Double-blind, Placebo Controlled Phase III Study of ODM-201 Versus Placebo in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer.
Patient choice
Paziente 1 Paziente 2
Età 60 80
Provenienza Verona Provincia di VR
Lavoro Impiegato Contadino
PSA screening Saltuario Mai
Clinica Dolore lombare recente Dolori lombari da tempo Sedi di malattia 4 lesioni ossee (3+1) 4 lesioni ossee (3+1)
Gleason Score 4+5 4+4
Valore di PSA 17 8
Patient choice
Patient choice
Presented By Karim Fizazi at 2017 ASCO Annual Meeting
